Type 1 diabetes represents the end result of a devastating decision on the part of CD4+ and CD8+ T cells specific for beta cell antigens to chose pathogenesis rather than zero tolerance. This Program Project grant brings together three investigators that have established an on-going collaboration with the goal of understanding the basis for this decision, and identifying immunotherapies that will prevent such autoimmunity. In Project 1, Dr. Webb will determine how the initial conditions which naive CD4+ cells become activated ultimately influence their migration and pathogenic properties in vivo.. The proposed studies will define the regulatory molecules that contribute to these decisions. Neutralizing antibodies and cytokine/chemokine deficient mice will be used to identify molecules that trigger inflammation in the pancreas. In Project 2, Dr. Sherman focuses on pathways that induce CD8+ T cells that have low affinity for a self-antigen expressed in the islets to become pathogenic. Potential external modulators of pathogenicity to be tested include strongly activating altered peptide ligands, the presence of differentially activated CD4 cells, viral infection, and the influence of a generally pro- inflammatory milieu. In Project 3, Dr. Sarvetnick will use NOD mice expressing individual cytokines in their islets to test the hypothesis that the cytokine milieu in which CD8+ cells are activated alter their pathogenic potential by affecting their longevity. The hypothesis will also be tested that the effect of type 1 and type 2 cytokines on CD8+ cells is opposite to that on CD4+ cells, such that type 2 cytokines promote disease. A collaborative goal of Drs. Sherman and Sarvetnick is to define the mechanism of protection from diabetes as induced by a GAD DNA vaccine. Preliminary experiments suggest prevention may occur through CD8 T cell tolerance.